Dronabinol is the United States Adopted name for .DELTA..sup.9 -tetrahydrocannabinol (THC): ##STR1##
Dronabinol recently was included in the United States Pharmacopoeia and currently is in use as an antiemetic for persons undergoing chemotherapy. Other therapeutic applications, including its use as an appetite stimulant in cachectic conditions, also are under investigation.
Previous processes for the preparation of dronabinol and related compounds have employed acid-catalyzed electrophilic condensation of a 5-alkylresorcinol such as 5-n-pentylresorcinol (commonly known as olivetol) and a menthadienol, followed by cyclization; see, e.g., Petrzilka et al., Helv. Chim. Acta, 52, 1102 (1969).
Often the condensation and cyclization are carried out sequentially, without isolation or purification of the intermediate cannabidiols, but this approach suffers from the production of water in the condensation step. This in turn leads to side-reactions during the subsequent cyclization; e.g., isomerization of the double bond from the .DELTA..sup.9 -position to the thermodynamically more stable but unwanted .DELTA..sup.8 -position. Thus the condensation/cyclization conditions employed by Petrzilka et al., supra, cause complete double-bond isomerization, necessitating two additional chemical steps to restore the double bond to the .DELTA..sup.9 -position. The overall yield of dronabinol having a purity greater than 96% thus was reported to be only 17-22% and at least two very tedious and careful chromatographic separations were required. See Razdan et al., JACS, 96, 5860 n.6(b) (1974).
Attempts have been made to absorb the water formed during the condensation step by using various drying agents (anhydrous magnesium sulfate, molecular sieves) Razdan et al., supra, U.S. Pat. No. 4,025,516 and U.S. Pat. No. 4,116,979]. Although on a small scale a 31% yield of reasonably pure dronabinol can be isolated using these techniques, the products are formed as a complex mixture. Moreover when carried out on larger scale, the product mixture still includes significant amounts of .DELTA..sup.8 -tetrahydrocannabinol. See e.g., Olsen et al., U.S. Pat. No. 4,381,399.
Stoss et al., Synlett, 1991, 553, describe a synthesis of dronabinol in which olivetol is condensed with cis-p-menth-2-ene-1,8-diol. See also European Patent Application 494,665. The 6,12-dihydro-6-hydroxycannabidiol intermediate formed, namely 1,3-dihydroxy-2-[6-(2-hydroxyprop-2-yl)-3-methylcyclohex-2-en-1-yl]-5-pent ylbenzene, is cyclized with zinc bromide or zinc chloride. An inherent disadvantage of using 6,12-dihydro-6-hydroxycannabidiol involves the water which is formed during the production of .DELTA..sup.9 -tetrahydrocannabinol since, as noted above, water can lead to unwanted side reactions including double-bond isomerization. Although the product after chromatography was stated to contain less than 4% impurities, the level of .DELTA..sup.8 -tetrahydrocannabinol impurity, which is difficult to separate, was not given.
Other processes are generally unsatisfactory for use on an industrial scale because of either or both of the relatively low yields and the formation of large amounts of closely related or isomeric by-products, e.g., abnormal, disubstituted, iso-, cis-, and .DELTA..sup.8 -analogs. Pharmaceutical grade material thus becomes extremely difficult to obtain without resorting to time-consuming, sophisticated, and costly chromatographic purifications; See e.g., Olsen et al, U.S. Pat. No. 4,381,399.
Methyl olivetolate, alternatively named as methyl 2,4-dihydroxy-6-n-pentylbenzoate, has been described as an intermediate in the synthesis of olivetol (see Brossi et al., U.S. Pat. No. 3,919,322) and might be expected, on electronic and statistical grounds, to be less reactive than olivetol towards electrophilic condensation, but to react with greater regiospecificity in producing methyl cannabidiolate: ##STR2##
This favorable regiospecificity has in fact been observed experimentally by Crombie et al., J. Chem. Res. (S) 114, (M), 1301-1345 (1977) who reported that upon condensation with p-mentha-2,8-dien-1-ol, methyl olivetolate gave methyl cannabidiolate in 89% glc yield (39-56% isolated yield). These yields all are based upon unrecovered starting material, methyl olivetolate. Similar regiospecificity was observed by Crombie et al., Phytochemistry, 16, 1413 (1977) in further studies of this system, although the reaction conditions and product yields varied. Condensation of the corresponding ethyl ester, ethyl 2,4-dihydroxy-6-n-pentylbenzoate, with the same terpene produced up to 63% of the corresponding ethyl cannabidiolate, again based upon unrecovered starting material. In contrast, when olivetol itself was subjected to a similar condensation under a varisty of conditions it consistently yielded less cannabidiol than the corresponding "ortho" isomer. Petrzilka et al., Helv. Chim. Acta, 52, 1102 (1969).
Attempted cyclization of methyl cannabidiolate with p-toluenesulfonic acid, however, was .found by Crombie et al., J. Chem. Res. supra, to produce only about 20% of the desired methyl .DELTA..sup.9 -tetrahydrocannabinolate-B: ##STR3##
The desired product was accompanied by a large quantity and variety of undesired side products including 14% methyl .DELTA..sup.9 -tetrahydrocannabinolate-A: ##STR4##
In addition, the reaction product included 5% methyl .DELTA..sup.8 -tetrahydrocannabinolate-A; 8% methyl .DELTA..sup.8 -tetrahydrocannabinolate-B; and 4% of a mixture of methyl isotetrahydrocannabinolate-A and methyl isotetrahydrocannabinolate-B. Moreover, cyclization of methyl cannabidiolate with p-toluenesulfonic acid under somewhat different conditions was found to produce complete double bond isomerization, producing a mixture of methyl .DELTA..sup.8 -tetrahydrocannabinolate-A and methyl .DELTA..sup.8 -tetrahydrocannabinolate-B with the former predominating {see Edery et al., Arzneim. Forsch. (Drug Res.), 22, 1995 (1972)}. Neither methyl .DELTA..sup.9 -tetrahydrocannabinolate-A nor methyl .DELTA..sup.9 -tetrahydrocannabinolate-B was found to be produced.
Chan et al., Tetrahedron Letters, 23, 2935 (1982), report to have obtained methyl .DELTA..sup.9 -tetrahydrocannabinolate-A directly from methyl olivetolate and p-mentha-2,8-dien-1-ol using boron trifluoride and reaction conditions very similar to those of Crombie et al., Phytochemistry, supra. Numerous attempts to repeat Chan's results have been unsuccessful and rather than producing methyl .DELTA..sup.9 -tetrahydrocannabinolate-A, give only methyl cannabidiolate in moderate yield.
Thus previous syntheses of dronabinol utilizing a cannabidiolate intermediate have failed to describe conditions under which the cannabidiolate can be efficiently cyclized to a suitable .DELTA..sup.9 -tetrahydrocannabinolate.